Investigating the Relationships between the Structure and Cytotoxicity of Ionic Liquids in the Context of Cell Lines Being Affected

Abstract Current quantitative structure–activity relationship (QSAR) models of ionic liquid (IL) cytotoxicity are generally developed for specific biological systems and cannot be assumed to transfer across cell types. Here, we evaluated 81 ILs spanning eight cationic head groups and 13 anions in HEK293T, CaCo-2, and DF-1 cell lines. The alkyl side chain length was the dominant structural determinant within homologous series, whereas cation, anion, and functionalization effects were most evident among ILs with shorter alkyl side chains. Mechanistic assays with 1-alkyl-3-methylimidazolium chlorides revealed distinct 24-h cellular response profiles in HEK293T and DF-1 cells, including different patterns of membrane permeabilization, apoptosis, and mitochondrial membrane potential changes. Descriptor-cytotoxicity correlations were strong within homologous imidazolium series but were less transferable across other structural comparisons. These results show that structure-based models can be informative within a defined chemical and cellular domain, but the cell type and cytotoxic response must be considered when extrapolating the IL cytotoxicity and assessing the safety of ILs proposed as greener process media.